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Pot withdrawal eased for dependent users | YaleNews

Withdrawal symptoms are marked by craving for marijuana, irritability, anger, depression, insomnia, and decrease in appetite and weight. In 2015, about 4 million people in the United States met the diagnostic criteria for a cannabis use disorder, and almost 150,000 voluntarily sought treatment for their cannabis use.
According to recent national data, approximately one-third of all current cannabis users meet diagnostic criteria for CUD.

Effective new target for mood-boosting brain stimulation found -- ScienceDaily

"Stimulation induced a pattern of activity in brain regions connected to OFC that was similar to patterns seen when patients naturally experienced positive mood states," says Vikram Rao, of the University of California, San Francisco. "Our findings suggest that OFC is a promising new stimulation target for treatment of mood disorders."
The team led by Rao and Kristin Sellers in the lab of Edward Chang studied 25 patients with epilepsy who had electrodes placed in the brain for medical reasons to pinpoint the origin of their seizures. Many of those patients also suffered from depression, which is often seen in people with epilepsy. With the patients' consent, Chang's team took advantage of those electrodes to deliver small electrical pulses to areas of the brain thought to be involved in regulating mood.
Previous studies have explored deep brain stimulation (DBS) for mood disorders, but its success depends critically on target selection. Targets in other mood-related areas deep in the brain hadn't always led to reliable improvements.
In the new study, the researchers focused their attention and the electrical stimulation on the OFC. The OFC is a key hub for mood-related circuitry. But it's also widely regarded as one of the least well-understood brain regions.
"Although OFC is a more superficial target, it shares rich interconnections with several brain regions implicated in emotion processing," Sellers says. That made this relatively small brain area an attractive target for therapeutic stimulation.
The researchers used the implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. Those studies found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. The changes in brain activity the researchers observed after stimulation closely resembled those seen when people are in a good mood.

May A.I. Help You? - The New York Times

In a study with 70 young adults, Darcy found that after two weeks of interacting with the bot, the test subjects had lower incidences of depression and anxiety. […]Last spring, when Darcy put Woebot online, free to all, its use immediately exploded; in the first week, more than 50,000 people talked to it. (“Do you realize,” Ng told Darcy, “that Woebot spoke to more people today than a human therapist could in a lifetime?”) Nowadays, Woebot exchanges between one and two million messages a week with users, ranging from divorcées to the bereaved to young men, a population that rarely seeks treatment. Many tell Darcy that it’s easier to talk to a bot than a human; they don’t feel judged.

Then, to compare results across the unique brains and distinct electrode placements of all 21 research participants, the researchers mapped each subject's ICNs onto neural connectivity diagrams. Comparing these standardized records of network activity across subjects revealed several "cliques" -- groups of brain regions that repeatedly became synchronized at specific frequencies, and were therefore likely to represent functional brain networks.
One such clique was highly active and coordinated in 13 research participants, all of whom had also scored high on a psychological assessment of baseline anxiety conducted prior to the start of the study. In these same individuals, changes in the activity of this brain network were also highly correlated with day-to-day bouts of low or depressed mood. This mood-related network was characterized by so-called beta waves -- synchronized oscillations between 13 and 30 cycles per second -- in the hippocampus and amygdala, two deep brain regions which have long been linked, respectively, to memory and to negative emotion.
Sohal said the research team was at first taken aback by the clarity of the finding. "We were quite surprised to identify a single signal that almost completely accounted for bouts of depressed mood in such a large set of people," said Sohal. "Finding such a powerfully informative biomarker was more than what we'd expected at this stage of the project."
Surprisingly, this powerful link between of mood-associated beta waves in the amygdala and hippocampus was entirely absent from eight other research participants, all of whom had comparatively low preexisting anxiety, suggesting new questions about how the brains of people prone to anxiety may differ from others in how they process emotional situations.

"Our study reveals, for the first time, the existence of a neuronal population of 'reward neurons' amid the sensory cells of the right branch of the vagus nerve," says Ivan de Araujo, DPhil, Senior Faculty in the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the paper. "We focused on challenging the traditional view that the vagus nerve is unrelated to motivation and pleasure and we found that stimulation of the nerve, specifically its upper gut branch, is sufficient to strongly excite reward neurons lying deep inside the brain."
The branches of the vagus nerve are intricately intermingled, making it extremely difficult to manipulate each organ separately. To address this challenge, the research team employed a combination of virally delivered molecular tools that allowed them to exclusively target the vagal sensory neurons connected to the stomach and upper intestine.
Specifically, researchers combined different viruses carrying molecular tools in a way that allowed them to optically activate vagal neurons connected to the gut while vagal neurons leading to other organs remained mute. The approach, a state-of-the-art technique known as "optogenetics," allows investigators to use light to manipulate the activity of a prespecified set of neurons.
The study revealed that the newly identified reward neurons of the right vagus nerve operate under the same constraints attributed to reward neurons of the central nervous system, meaning they link peripheral sensory cells to the previously mapped populations of reward neurons in the brain. Strikingly, neurons of the left vagus were associated with satiety, but not with reward. The research team's anatomical studies also revealed, for the first time, that the right and left vagal branches ascend asymmetrically into the central nervous system.

In depression the brain region for stress control is larger -- ScienceDaily

So far, it is known that people more predisposed to depression show a dysregulation of the endogenous stress response system, otherwise known as the hypothalamic-pituitary-adrenal axis (HPA axis), which is normally triggered when we are faced with a stressful situation. This response increases the amount of cortisol, providing the body with more energy when faced with a potential threat or challenge. Once the challenging situation has passed, several control mechanisms in the HPA axis normally ensure the system returns to a balanced state.
In people who suffer with depressive disorder or who are more predisposed, this is not the case. Instead, a malfunction of the feedback mechanism results in a stress response operating at full throttle, even when there is no apparent stressful situation. Until now, the underlying reason for this hyperactive stress response system and the role of the hypothalamus as its overall control unit has remained unclear.

Breakthrough brain research could yield new treatments for depression -- ScienceDaily

According to Shanechi, for clinical practitioners, a powerful decoding tool would provide the means to clearly delineate, in real time, the network of brain regions that support emotional behavior.
"Our goal is to create a technology that helps clinicians obtain a more accurate map of what is happening in a depressed brain at a particular moment in time and a way to understand what the brain signal is telling us about mood. This will allow us to obtain a more objective assessment of mood over time to guide the course of treatment for a given patient," Shanechi said. "For example, if we know the mood at a given time, we can use it to decide whether or how electrical stimulation should be delivered to the brain at that moment to regulate unhealthy, debilitating extremes of emotion. This technology opens the possibility of new personalized therapies for neuropsychiatric disorders such as depression and anxiety for millions who are not responsive to traditional treatments."

One key insight from the research, Alhanai notes, is that, during experiments, the model needed much more data to predict depression from audio than text. With text, the model can accurately detect depression using an average of seven question-answer sequences. With audio, the model needed around 30 sequences. "That implies that the patterns in words people use that are predictive of depression happen in shorter time span in text than in audio," Alhanai says. Such insights could help the MIT researchers, and others, further refine their models.

Exercise as Medical Treatment for Depression - ScienceDirect

The investigators randomized 101 patients with various degrees of depression into 3 treatment groups: sertraline (50 to 200 mg), group exercise 3 times per week, or placebo. Baseline depressive symptoms were assessed both by the Hamilton Rating Scale for Depression and a structured interview. Approximately one-half of the patients had major depression. At 4-month follow-up, there were comparable reductions in depressive symptoms among the patients who received sertraline and those who underwent exercise, and both groups had greater reductions in depressive symptoms compared with placebo. These results are concordant with those of 2 prior randomized studies these investigators performed to compare exercise with antidepressant medication in noncardiac subjects with depression (18, 19).

What’s more, the group found that the serotonin neurons themselves were more complex than originally thought. Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate – making them one of the few known examples of neurons in the brain that release two different chemicals.
“It raises the question of whether we should even be calling these serotonin neurons because neurons are named after the neurotransmitters they release,” Ren said.
Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. Luo’s team has identified two groups, but there could be many others.
In fact, Robert Malenka, a professor and associate chair of psychiatry and behavioral sciences at Stanford’s School of Medicine, and his team recently discovered a group of serotonin neurons in the dorsal raphe that project to the nucleus accumbens, the part of the brain that promotes social behaviors.

Depressed patients see quality of life improve with nerve stimulation: Study focuses on people not treated effectively with antidepressants -- ScienceDaily

The researchers followed 328 patients implanted with vagus nerve stimulators, many of whom also took medication. They were compared with 271 similarly resistant depressed patients receiving only treatment as usual.
In assessing quality of life, the researchers evaluated 14 categories, including physical health, family relationships, ability to work and overall well-being.
"On about 10 of the 14 measures, those with vagus nerve stimulators did better," Conway said. "For a person to be considered to have responded to a depression therapy, he or she needs to experience a 50 percent decline in his or her standard depression score. But we noticed, anecdotally, that some patients with stimulators reported they were feeling much better even though their scores were only dropping 34 to 40 percent."
A vagus nerve stimulator is surgically implanted under the skin in the neck or chest. Stimulation of the vagus nerve originally was tested in epilepsy patients who didn't respond to other treatments. The FDA approved the device for epilepsy in 1997, but while testing the therapy, researchers noticed that some epilepsy patients who also had depression experienced fairly rapid improvements in their depression symptoms.

The researchers examined data from 1,017 participants who were included in the March 2017 public data release from the Human Connectome Project. They found that both poor sleep quality and depressive symptoms were associated with neural connectivities involving the lateral orbitofrontal cortex, the dorsolateral prefrontal cortex, the cingulate cortex, and the precuneus.
“Our analysis shows that the functional connections between the areas of the brain associated with short-term memory, the self, and negative emotions are increased in both poor sleep and depressive participants. So people with poor sleep or depression may focus too much on the negative things and dwell on bad thoughts, which leads to a poor quality of sleep,” Feng told PsyPost.

Getting to the Roots of Pessimism - Neuroscience News

MIT neuroscientists have now pinpointed a brain region that can generate this type of pessimistic mood. In tests in animals, they showed that stimulating this region, known as the caudate nucleus, induced animals to make more negative decisions: They gave far more weight to the anticipated drawback of a situation than its benefit, compared to when the region was not stimulated. This pessimistic decision-making could continue through the day after the original stimulation.
The findings could help scientists better understand how some of the crippling effects of depression and anxiety arise, and guide them in developing new treatments.
“We feel we were seeing a proxy for anxiety, or depression, or some mix of the two,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study, which appears in the Aug. 9 issue of Neuron. “These psychiatric problems are still so very difficult to treat for many individuals suffering from them.”

The Lancet Psychiatry: Exercise linked to improved mental health, but more may not always be better | EurekAlert! Science News

Exercising for 30-60 minutes was associated with the biggest reduction in poor mental health days (associated with around 2.1 fewer days of poor mental health compared with people who did not exercise). Small reductions were still seen for people who exercised more than 90 minutes a day, but exercising for more than three hours a day was associated with worse mental health than not exercising at all. The authors note that people doing extreme amounts of exercise might have obsessive characteristics which could place them at greater risk of poor mental health.

Lack of a Single Molecule May Indicate Severe and Treatment Resistant Depression - Neuroscience News

Naturally produced by the body, LAC performs a number of crucial tasks in the brain. For example, the molecule regulates energy metabolism and interacts with DNA to promote the expression of important genes. Specifically, it acts on a gene that controls levels of the neurotransmitter glutamate–a chemical implicated in almost everything that the brain does.
McEwen, the Alfred E. Mirsky Professor, and Nasca, a postdoctoral fellow of the American Foundation for Suicide Prevention, have studied the link between LAC and mood disorders using animal models. In one study, they showed that LAC supplements ameliorate depressive symptoms in mice by reversing brain-cell impairment caused by an excess of glutamate. In a separate rodent study, they observed that LAC treatment reduces depressive behavior and stress-associated neural dysfunction in the medial amygdala, a brain region involved in social interactions. These findings strongly suggest that LAC deficits contribute to a depression-like state in mice, leading the scientists to wonder whether the molecule plays a similar role in humans.

These results show that repeated social defeat stress activates microglia in the medial prefrontal cortex via the innate immune receptors TLR2/4. This triggers the expression of inflammation-related cytokines IL-1? and TNF?, leading to the atrophy and impaired response of neurons in the medial prefrontal cortex, and causing depressive behavior.
Professor Furuyashiki says: "These findings demonstrate the importance of neural inflammation caused by the innate immune system for stress-induced depression. This could lead to the development of new antidepressant medication targeting innate immune molecules."

Video: The Underlying Mechanisms of Depression

While it’s likely that there may be more going on with depression than just inflammation by itself, it could be an incredibly useful lens through which to look at promising avenues to potentially treat or prevent it, since controlling systemic inflammation shows promise as being both important for longevity and health in general.
Moreover, inflammation can be clinically monitored by well-known biomarkers for systemic inflammation, making it amenable to potentially tracking therapeutic success: the risk of major depression has been shown to increase by 44% for each standard deviation increase in log c-reactive protein.

Suicide is a national epidemic. We need to treat it like one. - The Washington Post

These two treatments are obviously different, but they both point to an entirely new chemical axis in the brain that could be targeted to treat depression: the glutamine/glutamate axis. Commonly abbreviated Glx, these chemicals are suppressed in people with severe depression and post-traumatic stress disorder (PTSD) and do not increase when patients take serotonin-targeting antidepressants.
The company I lead is working to develop drugs to raise Glx without the damaging side effects of ketamine or ECT. The science is promising: The FDA recently issued a biomarker letter of support, its first in psychiatry under the 21st Century Cures Act, recognizing that an increased level of Glx correlates with decreased levels of depression and that drugs targeting Glx are linked to a reduction in depression and suicidal ideation.

The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa.

The immune system and the pathogenesis of depression

During chronic infections and other chronic medical conditions associated with intense immune activation, the sickness behaviour syndrome can develop into a depressive episode.
Studies have found that certain cancer and hepatitis c therapies, which often involve the use of cytokines, have been associated with the development of flu-like depressive symptoms. The causal role of the cytokines has been established by the fact that the depressive symptoms appear almost immediately after cytokine administration and disappear shortly after cytokine treatment is terminated.

The immune system and the pathogenesis of depression

There is bidirectional communication between the HPA axis and the immune system. Cytokines activate the HPA axis and thus lead to the release of cortisol, the stress hormone, which ordinarily suppresses the immune response. Cortisol also inhibits its own release and thus the body is able to maintain a stable immune response through a tightly regulated feedback inhibition system. This regulation mechanism seems to be dysfunctional in depressive disorders and is thought to occur because of cytokine mediated receptor resistance to cortisol, thus impairing feedback inhibition. This essentially means that cytokines make cortisol unable to act on the receptors that would inhibit its release. Long story short — the HPA axis is hyperactive because of cytokines, leading to a chronic stress response because cytokines impair the body’s ability to regulate it — thus leading to depressive symptoms.

The real truth isn't found within the published paper but rather within a busy table on page 142 of the online appendix. It is here where the authors report what we want: the actual difference between drugs and placebo, before and after treatment, on the depression rating scales. Here we see that the Cohen's d standardized mean difference effect sizes range from a low of 0.19 to a high of 0.62 with amitriptyline. Thus, amitriptyline exceeds the clinically meaningful threshold of 0.50, with a traditional meta-analytic method. No other drug does so, with the closest second place being fluvoxamine, with a Cohen's d value of 0.44.
Looking at all of the agents, 10 drugs have Cohen's d values less than 0.30, which is very small and clinically meaningless, whereas four have effect sizes from 0.30 to 0.34. Thus, 74% (14/19) of antidepressants clearly have little or no clinically important benefit in this analysis (for some reason, no data are provided in this table with two of the drugs). Four drugs have effect sizes of 0.37-0.44, and as noted, one agent exceeds the 0.50 threshold (amitriptyline).
Perhaps a clearer conclusion than anything else is the well-proven fact that the tricyclic antidepressants are more effective than newer agents (there were no monoamine oxidase inhibitors in this meta-analysis).

Rare mutation of gene carried by Quebec family gives insight into how the brain is wired: Brain scans could further understanding of psychiatric disorders, brain's reward system -- ScienceDaily

By scanning the brain of 20 family members who share an altered copy of DCC, the researchers found less connectivity between the areas where dopamine neurons originate (the substantia nigra and ventral tegmental area) and their target sites, such as the striatum and frontal cortex. One of these target sites -- the striatum -- was also smaller.
"It's very interesting because we were able to show that this DCC gene alteration induces similar changes to the brain in both mice and humans," says Cecilia Flores.
Because the brain systems affected by the gene influence responses to rewards, it was not surprising to see that the family members with the DCC mutation also have lower impulsivity traits and are less likely to smoke cigarettes. Indeed, an increasing number of studies, including those by Professor Flores' team, link DCC to psychiatric conditions.
"Because the gene affects the brain's dopamine pathways, which are implicated in schizophrenia, addiction and depression, our study potentially helps us understand how these disorders arise.

Early birds less prone to depression: Largest study yet links chronotype to mental health -- ScienceDaily

In 2009, all the participants included in the study were free of depression. When asked about their sleep patterns, 37 percent described themselves as early types, 53 percent described themselves as intermediate types, and 10 percent described themselves as evening types.
The women were followed for four years to see who developed depression.
Depression risk factors like body weight, physical activity, chronic disease, sleep duration, or night shift work were also assessed.
The researchers found that late chronotypes, or night owls, are less likely to be married, more likely to live alone and be smokers, and more likely to have erratic sleep patterns.
After accounting for these factors, they found that early risers still had a 12 -- 27 percent lower risk of being depressed than intermediate types. Late types had a 6 percent higher risk than intermediate types ( this modest increase was not statistically significant.)
"This tells us that there might be an effect of chronotype on depression risk that is not driven by environmental and lifestyle factors," said Vetter.

A bad night's sleep linked to suicidal thoughts the following day in people with depression

The researchers found that short sleep duration and poor sleep quality both predicted higher severity of suicidal ideation on the following day, even after controlling for anxiety and depression symptom severity. “However, suicidal thoughts did not predict sleep problems the following night,” Littlewood noted.